Parp Inhibitors As Single Agents
According to the preclinical rationale described above, PARPi were firstly developed as single agents in mCRPC. The main clinical studies are summarized in Table .
Table 1 Phase II or III trials using PARP inhibitors alone to treat prostate cancers
Olaparib
TOPARP studies confirmed that Olaparib used alone was more efficient in HRR deficient mCRPC. Moreover, the efficacy in terms of CRR seemed to be higher for effector genes of the HRR system than sensors .
Niraparib
GALAHAD is a phase II study with a small number of patients. Thus, results on efficacy need to be interpreted cautiously. As for olaparib, niraparib seems to be more efficient in BRCA-altered patients. Efficacy is in the same order of magnitude as olaparib even if we would expect a greater effect in a pure biallelic population. Toxicity was manageable and similar to olaparib.
Three other ongoing phase II studies evaluating niraparib as monotherapy are reported in Table . One for mCRPC and two for localized prostate cancer. To date, there is no phase III study investigating niraparib as monotherapy.
Rucaparib
The TRITON-3 study is an ongoing phase III trial comparing rucaparib versus abiraterone, enzalutamide or docetaxel after 1 NHT but no chemotherapy, for patients with mCRPC and a deleterious mutation of BRCA1/2 or ATM .
Talazoparib
Patterns Of Response In Brca
Of the 32 patients in the BRCA1/2 subgroup identified by targeted NGS, 13 had a germline mutation and 19 a tumor-only pathogenic alteration . The composite response rates to olaparib in these BRCA1/2 subgroups were similar for those with germline mutations and those with alterations detected only in tumor DNA .
Responses to olaparib based on the origin and type of the qualifying genomic alterations
| . |
|---|
Considering all patients with biallelic loss , the median rPFS and median OS for patients with BRCA1/2 biallelic loss was 9.7 and 18.9 months, respectively, compared with a median rPFS and median OS of 5.6 and 14.6 months for those without detectable biallelic loss .
These data suggest that most tumors with BRCA mutations are likely to have biallelic loss, even if the most commonly used NGS assays may miss detecting some events leading to complete loss-of-function, such as complex rearrangements. Yet, our data largely refer to BRCA2 alterations, as only 2 patients had BRCA1 alterations. Patients with mCRPC with BRCA2 homozygous deletion had superior rPFS and OS outcomes from PARP inhibition, suggesting that olaparib resistance may be harder to evolve in these tumors.
Expert Knowledge Share: Incorporating Parp Inhibitors Into Prostate Cancer Clinical Practice
On-demand video replay and slide set now available
On-demand video replay and slide set now available
Prof. Fred Saad, Assoc. Prof. Tanya Dorff, Prof. Gerhardt Attard, Prof. Neeraj Agarwal
In our recent Expert Knowledge Share, world-renowned experts discussed case studies, reviewed the latest data and shared their views. The on-demand video replay and slide set are available below. Accredited e-learning programme coming soon.
- PARP inhibitors are an important part of the treatment strategy for mCRPC patients
- mCRPC patients who harbour HRR mutations benefit from PARPi monotherapy following progression on prior novel hormonal agents
- Treatment with PARP inhibitors plus novel hormonal agents can provide combination benefits in mCRPC patients with or without HRR mutations
- The future treatment landscape for prostate cancer patients will likely include the earlier introduction of PARPi’s and treatment beyond patients with HRR/DRR mutations
Prof. Fred Saad
City of Hope Comprehensive Cancer Center
United States
Assoc. Prof. Tanya Dorff has received financial support/sponsorship for research support, consultation, or speaker fees from the following companies:
AstraZeneca, Astellas, Exelixis, Janssen and SeaGen.
University College London Cancer Institute
United Kingdom
Prof. Gerhardt Attard has received financial support/sponsorship for research support, consultation, or speaker fees from the following companies:
Astellas, AstraZeneca, Bayer, Janssen, Novartis and Pfizer.
Read Also: How Do They Do A Biopsy Of Your Prostate
Other Prostate Cancer Subgroups That May Benefit From Parp Inhibitors
As discussed above, PARP inhibition has demonstrated efficacy in patients with CRPC who exhibit mutations in BRCA1, BRCA2, and ATM on the basis of the TOPARP-A trial. However, it is unclear if there are additional subgroups that might derive benefit from PARP inhibitor monotherapy. One potential candidate is TMPRSS2-ETS which has been noted to exhibit alterations in 50% of prostate cancers found in Caucasians. Given the proposed involvement of PARP1 in the formation of a fusion gene between a transcription factor in the ETS family and the androgen responsive gene TMPRSS2, there was suggestion that this might represent a cohort likely to have increased sensitivity to PARP inhibition outside of its role in DNA repair through prevention of this interaction. This is supported by the pre-clinical observation that olaparib inhibits growth of ETS mutated cell lines.
Targeting Noncanonical Ddr Genes
Although the beneficial effects of treating patients with BRCA1/2 mutations are evident, a wider patient population with mutations in other DDR genes may benefit from treatment with PARP inhibitors. As with BRCA, the ideology behind treating patients harboring mutations in noncanonical DDR genes remains rooted in the concept of synthetic lethality: using lossoffunction mutations present in tumors in combination with inhibition of the cell’s ability to detect and respond to DNA damage in order to induce a lethal event. Several studies investigating the effects of using PARP inhibitors to treat PCa, including the trials discussed above, have reported responses in patients with mutations in nonBRCA DDR genes however, less attention has been given to these other genes. A recent study using unsupervised clustering of wholegenome sequencing data found that 7 of 22 patients clustered in a HRdeficient category did not have a biallelic BRCA inactivation . Although individual mutation frequencies may be low, understanding which genes and mutational subtypes most benefit, as well as the mechanisms by which these noncanonical DDR genes respond to PARP inhibition, would considerably increase the patient population considered for PARP inhibitor treatment across other types of cancer.
Don’t Miss: Side Effects Of Having Prostate Removed
Parp Inhibitor Monotherapy In Prostate Cancer
Tables 1 and 2 detail the studies evaluating PARP inhibitor monotherapy in metastatic castration-resistant prostate cancer . Although recent evidence is supportive of the earlier use of combined therapy with PARP inhibitors, monotherapy in second or subsequent line settings remains the most established method of using these agents. A meta-analysis of trials evaluating PARP inhibitor monotherapy reported significant improvement in progression-free survival and overall survival with fixed effects but not random effects models, perhaps stemming from heterogenous patient populations .
Table 1::
| Study |
|---|
| – | – |
NHT: Novel hormonal therapy , HRD: Homologous repair deficient, HRR: Homologous recombination repair, mCRPC: Metastatic castration resistant carcinoma prostate, ORR: Overall response rate, OS: Overall survival, PFS: Progressionfree survival, and PRR: PSA response rate
Parp Inhibitors For Prostate Cancer
Early-stage prostate cancer is very treatable with surgery and radiation therapy. Once the cancer spreads, it becomes harder to stop. Late-stage prostate cancer treatments like chemotherapy and hormone therapy can eventually stop working.
PARP inhibitors are a new kind of prostate cancer treatment called a targeted therapy. The goal of targeted therapy is to kill cancer cells without harming healthy cells.
Unlike chemotherapy and hormone therapy, which kill cancer cells or stop them from growing, PARP inhibitors block an enzyme prostate cancer cells need to repair themselves. When damaged cancer cells can’t fix themselves, they die.
PARP inhibitors can improve survival in men whose prostate cancer isn’t responding to hormone therapy and who have certain gene changes.
Before you have this treatment, it’s important to understand what it does and how it might help you.
Don’t Miss: Can You Feel Prostate Cancer
Potential Mechanisms Of Resistance
Increased RAD51 activity, either through downregulation of inhibitors such as EMI1/DDB2 or through upregulation of the TOP1 activator, allows HRR to bypass BRCA1 or 2 functions and leads to resistance. Notably, bromodomain protein 4 overactivity leads to a similar rise in RAD51 activity which may be negated by using bromodomain inhibitors.
Another common mechanism of PARP inhibitor resistance observed in in vitro studies is reversion mutations.
A separate method of the resistance stems from replication fork stabilization downregulation of EZH2. PTIP/CHD4/ MELL 3- or 4-mediated reduction of MRE11 activity, FANCD2-mediated MRE11 suppression, SMARCAL1 deletion, or RADX deletion all lead to PARPi resistance in in vitro models through replication fork stabilization. While epigenetic mechanisms of PARPi resistance exist, they are yet to be targeted clinically.
Cell Lines And Reagents
Human prostate cancer lines DU145, 22Rv1, and LNCaP were purchased from ATCC and maintained in phenol red free RPMI 1640 supplemented with 10% heat inactivated FBS . The U2OS DR-GFP HR reporter cell line was a gift from Dr. Alan DAndrea and was maintained in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin . All cell lines were grown at 37°C in a 5% CO2 incubator.
Recommended Reading: What Is The Best Over The Counter Prostate Medicine
Biomarkers Associating With Parp Inhibitor Benefit In Prostate Cancer In The Toparp
Corresponding Authors:Corresponding Authors:
S. Carreira and N. Porta contributed equally and are joint first authors of this article.
Corresponding Authors:
Cancer Discov 2021 11:281227
Cancer Discov
Suzanne Carreira, Nuria Porta, Sara Arce-Gallego, George Seed, Alba Llop-Guevara, Diletta Bianchini, Pasquale Rescigno, Alec Paschalis, Claudia Bertan, Chloe Baker, Jane Goodall, Susana Miranda, Ruth Riisnaes, Ines Figueiredo, Ana Ferreira, Rita Pereira, Mateus Crespo, Bora Gurel, Daniel Nava Rodrigues, Stephen J. Pettitt, Wei Yuan, Violeta Serra, Jan Rekowski, Christopher J. Lord, Emma Hall, Joaquin Mateo, Johann S. de Bono Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov 1 November 2021 11 : 28122827.
Details Of The Magnitude Trial
The MAGNITUDE study was conducted in patients with mCRPC who had previously received no more than 4 months of abiraterone and prednisone. Patients were tested for HRR gene alterations, including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 genes, but were included in the trial whether they did or did not have mutations.
Patients were randomized to receive niraparib 200 mg once daily or placebo, plus abiraterone.
The primary endpoint was rPFS assessed by blinded independent central review in the BRCA1/2 subgroup and in all patients who were HRR positive.
There were 233 biomarker-negative patients, but enrollment was halted in this arm on the recommendation of the independent data monitoring committee after treatment failed to show any benefit, explained Chi. “No benefit was observed with niraparib plus abiraterone in patients who were HRR biomarker negative.”
The remaining 423 HRR biomarker-positive patients were followed for a median of 18.6 months.
Among patients with BRCA1/2 mutations, the median rPFS was 16.6 months with niraparib plus abiraterone vs 10.9 months for placebo .
For the whole HRR-positive population, the median rPFS was 16.5 vs 13.7 months , although the investigator-assessed rPFS was higher for combination therapy, at 19.0 months vs 13.9 months .
Secondary endpoints also favored the niraparib arm: prolonged time to initiation of cytotoxic chemotherapy , time to symptomatic progression , time to PSA progression , and overall response rate .
Don’t Miss: Super Beta Prostate Vs Prostagenix
Dna Damage Repair Mutations And Prostate Cancer
Mechanisms of DNA damage Repair and Repair Pathways
Eukaryotic cells have evolved at least 5 major DNA repair pathways for recognizing and repairing endogenous and exogenous sources of DNA damage for the purpose of maintaining genomic integrity.18,19 For example, alkylating agents, ionizing radiation, and reactive oxygen species can cause single-strand DNA breaks or single-base damage that is repaired by the base excision repair pathway, while ultraviolet radiation and chemical mutagens can cause DNA crosslinks and bulky base damages that are repaired by the nucleotide excision repair pathway. Important enzymes for both BER and NER pathways include the DNA polymerases. Base mismatches formed due to replication errors during DNA replication and recombination are repaired by the mismatch repair pathway mediated by key MMR proteins such as MLH1, MSH2, MSH6, and PMS2. Lastly, DNA double-strand breaks caused by ionizing radiation or collapsed replication forks, for example, are repaired by the DSB repair pathway through either homologous recombination repair for nonhomologous end joining, the latter of which includes mediators such as Ku70, Ku80, DNA-PKcs, XRCC4, LIG4, XLF, and APLF.
DDR Alterations in Prostate Cancer
In a cohort of 150 patients with mCRPC, whole exome and transcriptome sequencing of bone or soft tissue tumor biopsies showed higher frequencies of aberrations in BRCA2, BRCA1, and ATM than in primary prostate cancers.23 Notably, 12.7% of cases had loss of BRCA2 .
Understanding Hrr Gene Mutations
HRR mutations occur in approximately 20-30% of patients with mCRPC.4 HRR genes allow for accurate repair of damaged DNA in normal cells.5,6 HRR deficiency means the DNA damage cannot be repaired, and can result in normal cell death. This is different in cancer cells, where a mutation in HRR pathways leads to abnormal cell growth and therefore cancer. HRD is a well-documented target for PARP inhibitors. PARP inhibitors block a rescue DNA damage repair mechanism by trapping PARP bound to DNA single-strand breaks which leads to replication fork stalling causing their collapse and the generation of DNA double-strand breaks, which in turn lead to cancer cell death.6
Recommended Reading: What Are The Side Effects Of Prostate Cancer Radiation Therapy
Parp Inhibitors In Metastatic Prostate Cancer: When Who And How
- Received:Epub ahead of print: 2022-09-23,
How to cite this article: Pandey P, Sahoo RK. PARP inhibitors in metastatic prostate cancer: When, who, and how? Int J Mol Immuno Oncol, doi: 10.25259/IJMIO_19_2022
Parp Inhibition As Maintenance Therapy
Olaparib demonstrated improved progression-free survival of 11.2 months versus 4.3 months using placebo when used as maintenance therapy following completion of chemotherapy for platinum-sensitive recurrent ovarian cancer and has received approval for this indication in the European Union but not yet in the United States.12,17 Following recent reporting of data from SOLO2, a Phase III trial demonstrating significantly improved PFS in patients with a BRCA1/2 mutation receiving olaparib monotherapy in the maintenance setting, the United States Food and Drug Administration granted priority review of olaparib for this indication.18 In addition, the PARP inhibitor niraparib received FDA approval as maintenance therapy in women with platinum-sensitive recurrent ovarian cancer based upon the results of NOVA, a Phase III placebo-controlled trial demonstrating improved PFS in women with platinum-sensitive recurrent ovarian cancer regardless of BRCA1/2 mutation or HRD status.19
Also Check: What’s The Symptoms Of Prostate Cancer
Dna Damage Repair And Parp Inhibition
PARPs form a large class of 16 enzymes. PARP1 and PARP2 respond to DNA damage and facilitate the cell’s DDR response . In healthy cells, PARP1 recognizes and binds to DNA at the site of singlestrand breaks and doublestrand breaks . A series of structural allosteric changes of PARP1 follow, which allows for the recruitment of acceptor proteins and production of a negatively charged poly branched polymer composed of NAD+ that links the damaged site to surrounding chromatin in a process known as PARylation . The negative charge repulses PARP1 from the complex and acts as a target for DDR proteins and polymerases, including XRCC1, POL, and LIG3, for continuation of the damage repair response . Should the SSB repair process fail, an accumulation of SSBs leads to replication arrest, followed by potentially lethal DSB formations at collapsed replication forks. DSBs can also occur independently from failed SSB repair, as they are commonly the result of harmful ionizing radiation damage to the cell. Healthy cells have the ability to recognize and repair DSBs via one of the four main DSB repair pathways: homologous recombination , nonhomologous end joining , alternative NHEJ, or singlestrand annealing . In addition to SSBs, PARP1 can recognize DSBs and competes with the Ku protein complex and the MRN complex for localization at free DNA ends. Depending on the phase of the cell cycle, either the Ku protein complex or PARP1 will carry out NHEJ or altNHEJ, respectively .
Rucaparib Get Green Light In Hrr
Rucaparib received accelerated FDA approval in May 2020 for patients with mCRPC based on data from the phase 2 TRITON2 trial , a single-arm study that treated men with somatic or germline alterations in an HRR gene with rucaparib 600 mg twice daily.16,17 Among the 115 patients with a BRCA alteration with or without measurable disease, the objective response rate was 43.5% per independent radiology review, and 50.8% per investigator assessment.17 The confirmed prostate-specific antigen response rate was 54.8% .17
TRITON2 also included 78 patients with non-BRCA HRR gene alterations, including 49 with ATM, 15 with CDK12, and 12 with CHEK2 alterations. The findings in these patients suggest that some of the other fairly common HRR gene alterations found in mCRPC may not sensitize cells to PARP inhibition, as there were limited radiologic and PSA responses however, patients who harbored some less frequently observed alterations in HRR genes, such as PALB2, were found to derive some benefit from PARP inhibition .
Were waiting for data from the phase 3, Barata said. shows that patients benefit from rucaparib. When we put all these data together again, a biomarker-based approach. In addition to the ongoing phase 3 TRITON3 study assessing rucaparib as a monotherapy ,19 rucaparib is being studied in combination with enzalutamide as a first-line treatment for mCRPC in the phase 3 CASPAR trial .20
Don’t Miss: Elevated Prostate Levels Blood Test
Role Of Dna Damage Repair Genes In Prostate Cancer
2.2.1. DDR Mutations in Prostate Cancer
Classical studies show that germline mutations in HR DNA repair genes have been observed in approximately 1015% of patients with metastatic prostate cancer, while somatic mutations occur in 2025% of those patients .
Of these mutations, BRCA2 mutations are the most frequently found , while ATM , CHEK2 , and BRCA1 are other commonly altered genes involved in HRR .
Since DDR pathway alterations were seen at similar rates between localized and metastatic PCa, it has been speculated that PARPi may also have a therapeutic effect in localized PCa.
To support this hypothesis, a 2019 study by Kim et al. analyzed the DDR pathway alterations in localized PCa using The Cancer Genome Atlas public database. Their results highlighted that the DDR alteration rate was surprisingly higher than suggested by previous studies and was associated with shorter OS in men with postoperative HR features.
A recent systematic review of the prevalence of DNA-damage-response gene mutations in prostate cancer that summarizes the prevalence of DDR mutation carriers in the unselected PCa and familiar PCa populations confirms these findings .
BRCA1/2 genes are located at chromosomes 17q21 and 13q12, respectively. They are large genes consisting of 100 and 70 kb, respectively. They have an autosomal dominant inheritance pattern with incomplete penetrance.
2.2.2. Germline Mutations
The prevalence of germline mutations varies among countries and ethnic groups.